In recent months, as the monkeypox virus swept through Europe, the Americas and parts of Asia, researchers discovered a puzzling trend: A large proportion of monkeypox cases have been occurring in people with HIV.

A new paper, published last week in the CDC's Morbidity and Mortality Weekly, reviews 2,000 monkeypox cases in the first two months of the U.S. outbreak and finds that nearly 40% are in people with HIV. That tracks with what health authorities from the European CDC and the World Health Organization have reported – their data show that around 37-45% of reported cases have been identified in people living with HIV.

So why are there so many monkeypox patients with HIV? Health experts have an initial thought to answer that question and then three theories on key contributing factors – with a leading contender among them.

The first thing to consider, says a co-author of the paper, is that the current monkeypox outbreak is largely concentrated among the population of men who have sex with men – "gay, bisexual, same gender-loving," says Dr. John T. Brooks, chief medical officer for the CDC's monkeypox outbreak response. And that's the population that's already at risk for HIV.

But that alone doesn't explain the high rate, says Brooks. In the U.S., for example, 23% of men who have sex with men are estimated to be living with HIV – but among the 2,000 monkeypox patients whose data was analyzed in the study, 38% had HIV. "This fraction of [monkeypox cases in people with] HIV "is pretty extraordinary," he says.

Theory #1: Monkeypox is circulating in the same social and sexual networks where HIV spreads

What's likely the biggest contributing factor, say the researchers, has to do with sexual networks. Monkeypox, like HIV, spreads through sexual contact, and it's circulating among various networks of gay, bisexual and other men who have sex with men.

But it's the networks, not necessarily the HIV status, that are critical. "I think it speaks more to the sexual network and less for the serostatus [of being HIV positive]," says Dr. Demetre Daskalakis, deputy coordinator for the White House monkeypox response and a study co-author, "This is the social and sexual network [where] we're seeing monkeypox infections happening."

Others agree. "The early spread of monkeypox was associated with ... cultural events – parties and celebrations that involved sexual networks" among gay and bisexual men, says Dr. Melanie Thompson, an HIV physician and researcher in Atlanta. People returning from parties abroad seeded early monkeypox cases in U.S., where monkeypox has continued to spread from person-to-person "almost exclusively" through sexual contact, according to the CDC.

"You only have to have sex, or be sexually active, with one person to get monkeypox," Thompson says, but the risk of getting monkeypox is currently magnified in the population of men who have sex with men, where more monkeypox is circulating than in the general population.

Another statistic noted by the researchers is that 41% of monkeypox patients in the study population had a recent history of other sexually transmitted infections, such as chlamydia, gonorrhea or syphilis. This is a significant finding, says Brooks: "It speaks to the fact that this is a population that is sexually active, and through close, intimate contact – in this case, what appears to be sexual contact – are at risk for acquiring monkeypox," Brooks says.

What it means is that monkeypox, HIV and sexually transmitted infections have overlapping risk factors, and doctors should look out for all of them, says Brooks: "If you diagnose someone with monkeypox, you should be screening for HIV as well as sexually transmitted infections. Conversely, among persons at risk for HIV and sexually transmitted infections who are seeking care, you need to think monkeypox and consider evaluating folks for that."

Theory #2: Maybe HIV's impact on the immune system leads to more infections?

It's an open question: "Is there something about having and living with HIV that increases your risk for acquiring monkeypox?" says Dr. Boghuma Titanji, an infectious diseases physician and a virologist at Emory University, noting that HIV changes the immune system in ways that could increase a person's risk of contracting any infections in general.

Many of the monkeypox patients with HIV in the CDC study have well-controlled infections – most had received HIV treatment in the past year and 82% were virally suppressed, meaning they had low to no detectable levels of HIV in their blood. That leads, leading to Titanji to wonder whether there's an elevated risk for HIV patients in general and not just those that aren't receiving treatments.

The study also found that 8% of monkeypox patients with HIV were hospitalized – somewhat higher than the 3% rate of hospitalization for those without HIV. Still, it's not clear from the data whether they were more likely to have severe cases or if their doctors were being cautious, says Brooks. "We have no signal whatsoever right now that people who have well-controlled HIV are doing any worse than any other person who was diagnosed with monkeypox," he says, "People with HIV [in the study] were generally receiving excellent care and doing well."

Still, monkeypox can be very dangerous for patients who have untreated HIV, Titanji says – who are often seriously immunocompromised and may also be more likely to delay care, especially if they lack access to health insurance or high-quality care.

Theory #3: HIV patients may see doctors more often so monkeypox cases are more readily identified

Another reason why HIV patients are overrepresented among monkeypox cases could be "detection bias," says Brooks. In other words, someone who's living with HIV and taking medications for it probably sees a doctor regularly – and their doctor may be clued in to look for monkeypox.

"This is the group of care providers who initially were willing to take care of people with HIV," says Thompson, "Whereas many providers, unfortunately, have been unwilling to see people with monkeypox, that seems not to be the case among HIV care providers. And so we see in this report that a very high proportion of people with HIV are actually linked to care," which may mean they're able to get tested and treated at the first sign of a suspicious rash.

Still, the fact that the high rates of HIV among monkeypox patients show up not just in the U.S., but "across the board" in patients in different health care systems in Europe and around the world, suggests there's a pattern that extends beyond detection bias, says Titanji.

Final note: Given these possible reasons, what's the next step?

Identifying the trend [of a high rate of monkeypox in the HIV positive population] is just "the tip of the iceberg. It raises a lot of questions," Titanji says.

Even though behavior seems to be the key cause, there's not enough information yet to figure out how much each factor contributes to the trend, Brooks and Thompson say.

Even so, knowing that monkeypox and HIV are linked in some way can help steer resources to where they could have the greatest impact. Daskalakis, with the White House response, says they're sharing monkeypox guidance and sending vaccines to HIV clinics through the federally funded Ryan White HIV/AIDS program, which he says provides medical care and support to around half of people living with HIV in the U.S. They're also working with funding and education to integrate monkeypox into the streams of care for HIV and STI's, "where it belongs," Daskalakis says.

Future findings will help refine the response. "We're going to learn more as we go along," says Daskalakis. Still, it could take a while to determine how much behavior, biology and bias are driving the trend, or whether there are other contributing factors yet to be considered.